Recombinant interleukin 12 enhances cellular immune responses to vaccination only after a period of suppression.
Adjuvant use of recombinant murine IL-12 (rmIL-12) was examined in mice vaccinated with irradiated syngeneic tumor or allogeneic cells. rmIL-12 given to A/J mice vaccinated with irradiated SCK tumor cells engineered to secrete granulocyte/macrophage-colony-stimulating factor resulted in significantly better protection from tumor challenges 28 days after vaccination but, unexpectedly, severely compromised host protection 14 days after vaccination. Immune suppression was rmIL-12 dose dependent and manifested as reduced splenic CTL activity, stimulated cytokine release and ability to reject SCK cells. Transient immune suppression was also seen with rmIL-12 given during vaccination of C3H/HeN mice with irradiated K1735 melanoma cells and of C57BL/6 mice with irradiated allogeneic HKB cells. The period of suppression coincided with transiently reduced splenic T-cell mitogenic responses to concanavalin A and IL-2, suggesting that they may be causally related. Suppression appears to be due to impaired immune effector mechanisms rather than impaired host immunization, which is actually enhanced as evidenced by the enhanced reaction to immunogens when hosts are challenged later after rmIL-12 administration. Demonstration that rmIL-12, as it is frequently used, induces a transient period of impaired immune response that can compromise host protection suggests that the unquestioned effectiveness of rmIL-12 against murine tumors is primarily due to activation of mechanisms other than antigen-specific tumor immunity (e.g., antiangiogenic effects) and that use of human IL-12 should be monitored for similar effects.
Kurzawa
H
H
Cell and Molecular Biology Graduate Group, Philadelphia, Pennsylvania 19104, USA.
Wysocka
M
M
Aruga
E
E
Chang
A E
AE
Trinchieri
G
G
Lee
W M
WM
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D007111:Immunity, Cellular / Q000187:drug effects*; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008805:Mice, Inbred A; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013045:Species Specificity; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014611:Vaccination
D019496:Cancer Vaccines; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor